Older adults exhibit considerable heterogeneity of immune and health phenotypes. Many of them are surviving well beyond the median life spans of many populations and have exceptional health and performance. Healthy aging is likely to be dependent on unique mechanisms of immune homeostasis in old age. Preliminary studies with a cohort of elderly persons aged >85 years show (a) phenomenal induction of natural killer cell-related receptors (NKR) along lineages of T cells with identical T cell receptors (TCR);(b) NKR+ T cells are capable of combining TCR-independent and TCR-dependent immune effector pathways;(c) NKR+ T cells circulate in a systemic environment characterized by generalized up-regulation of humeral factors;and (d) favorable health without measureable physical/cognitive impairment is correlated with high frequencies of T cells expressing activating forms of NKRs along with elevated levels of immune-enhancing cytokines in the plasma. These data suggest that aging need not be synonymous with immune incompetence. A longitudinal study is hereby proposed to examine the extent of NKR diversification on T cells and the degree of corresponding up-regulation of humeral factors, and how they relate to health characteristics of older adults. Community-dwelling adults who are 65 years and older will be clinically monitored for changes in physical performance, cognitive performance, co-morbid conditions, T cell phenotypes, and serology and viral load to common lifelong persistent viruses. Considering the well- recognized functional insufficiency of TCR signaling with aging, complementary experimental studies will be conducted to directly evaluate the magnitude and quality of the shift from TCR-dependent to NKR-driven TCR-independent functions of T cells with further chronologic aging, and assess the immunologic properties of particular subsets of NKR+ T cells. Assessment of the functional diversity of NKR+ T cells, and a global examination of the systemic humeral milieu are envisaged to demonstrate a functionally distinct immune environment in old age, rather than a dysfunctional version of that seen in younger persons. Simultaneous assessment of health characteristics and immunologic parameters will help define NKR, serological, and cytokine signatures of preserved health;or conversely, those that would be indicative of failing health. These studies will be important for the development of alternative strategies to enhance protective immunity in elderly persons. PUBLIC HEALTH RELEVANCE: Older adults exhibit heterogeneity of immune and health characteristics, and many of them are surviving beyond the median life spans of many populations and have exceptional health. This study is being conducted to examine profiles of T cells, anti-viral serology, and systemic cytokines that are associated with either preserved health or ill-health among adults who are 65 years and older. Results will be important to the development of strategies to enhance protective immunity with aging.